A recent meta-analysis by Konstantinos Katsanos, MD, of Patras University Hospital, Rion, Greece, and colleagues—“Risk of major amputation following application of paclitaxel-coated balloons [PCBs] in the lower-limb arteries: A systematic review and meta-analysis of randomized controlled trials [RCTs],” published in the European Journal of Vascular and Endovascular Surgery (EJVES)—warns of a possible heightened risk of major amputation after the use of PCBs in lower-extremity arteries.
Vascular Specialist asked some of our nation’s leaders in the care of peripheral vascular disease to comment on the clinical implications of this study.
Jessica Simons, MD, associate professor, University of Massachusetts Medical School, Worcester, Massachusetts
Katsanos and colleagues conducted a systematic review and meta-analysis of existing data from RCTs on the effect of PCB use (in the femoropopliteal and infrapopliteal segments) on major amputation.
Using an incredibly rigorous methodology, they found compelling evidence for an increased hazard of major amputation associated with paclitaxel drug-coated balloons (DCBs) compared with plain balloon angioplasty. This effect was more pronounced among limbs treated for chronic limb-threatening ischemia (CLTI) as compared with intermittent claudication; among CLTI patients, they calculated a number-needed-to-harm of 35 limbs.
Katsanos and colleagues demonstrated a dose-response effect. They posited a plausible biologic mechanism, including a contrast with drug-eluting stents. They concluded by saying that further investigation into the benefits and risks of paclitaxel DCBs are needed. To me, the primary question that remains is: Do we really need more studies?
As I have read the evidence supporting paclitaxel DCBs, none of it has ever been strong enough to mitigate these more recent findings. Prior to this particular study, I could have imagined some CLTI patients in whom there could be some limited role, since that group is often focused on limb salvage rather than survival. But this new analysis compels me that there is neither benefit.
Caitlin W. Hicks, MD, associate professor, Johns Hopkins Hospital, Baltimore, Maryland
The newest meta-analysis of PCBs by Kastanos et al, published in EJVES last month, raises concern about the use of DCBs for the treatment of peripheral arterial disease (PAD) for the second time in three years, this time with respect to major amputation risk. While the first meta-analysis, published in the Journal of the American Heart Association (JAHA) in 2018, focused on PCBs and stents, the newest meta-analysis on the topic is specific to DCBs. Similar to the original article, my personal bias after reading the abstract was one of skepticism. That feeling didn’t change much after reading the full text.
For one, nearly half of eligible studies were excluded from the analysis. The stated inclusion criteria for the meta-analysis drew from RCTs with at least six months of follow-up, which included any type of PCBs used to treat PAD in the lower extremities, and reported counts of major amputation as an endpoint.
However, when you review the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) flow diagram that reports study exclusions, the first point that jumps out is that 19 studies were excluded for having zero major amputation events in both study arms. Only 21 studies were included in the final analysis, meaning that nearly 50% of eligible studies were excluded.
The authors performed a variety of sensitivity analyses to demonstrate replicability of their findings, but notably did not perform one including the studies with no major amputation events, which would have reduced the event frequency substantially and likely rendered the differences between treatment non-significant.
My second concern with this meta-analysis is the inclusion of technology that has been actively unapproved by the Food and Drug Administration (FDA). For example, BD’s Lutonix DCB for below-the-knee (BTK) applications was recently rejected by the FDA for the second time in 18 months due to concerns about both clinical effectiveness and safety, yet the data from Lutonix-BTK was included in the meta-analysis—contributing the second largest number of patients of all 21 studies evaluated.
There are currently no FDA-approved DCBs for BTK applications, but the meta-analysis includes data from seven infrapopliteal studies that contributed outcomes for 1,355 out of a total of 3,760 limbs. While U.S. approvals are not the be-all and end-all of technology, the FDA is notoriously one of the strictest regulatory bodies for new technology in the world, and the inclusion of devices that have been actively rejected by the FDA in the past is setting up the DCB group for failure.
My third main concern about this meta-analysis is the inclusion of patients with CLTI. The risk of major amputation is not the same for patients with claudication and CLTI. CLTI also comes in a variety of forms, and without some understanding of the extent of disease, comparing major amputation rates for a sample of patients with heterogenous forms of PAD is uninformed. It is notable that the risk of major amputation in trials limited to claudication patients was not different for DCBs compared to plain balloon angioplasty, although, strikingly, the authors do not report the crude risk in the claudication subgroup.
While I think it has been an important endeavor to raise the academic question of PCDs and their outcomes, the current available evidence does not convince me that current (FDA-approved) DCB devices increase the risk of major amputation full stop. I will continue to use them selectively in appropriate patients until either an RCT or real-world data that adjusts for baseline differences in patient risk suggests otherwise.
Katharine McGinigle, associate professor, University of North Carolina School of Medicine, Chapel Hill, North Carolina
I congratulate the international group of authors led by Katsanos on their recent publication in EJVES. Their systematic review and meta-analysis evaluating the risk of major amputation following application of PCBs in lower-limb arteries was performed with impeccable methods and raises important concerns. Based on 21 RCTs, they conclude that there appears to be a heightened risk of major limb amputation after the use of PCBs for femoropopiteal and/ or infrapopliteal revascularization.
The authors theorize that this may be due to downstream embolization and tissue deposition of paclitaxel that causes unsalvageable tissue damage, despite target vessel patency. I agree with the authors that this is concerning and that specific trials to evaluate limb salvage outcomes are needed. In the meantime, I must decide what to do in my practice, and those conclusions are harder to draw.
The real limitation of all meta-analyses—including this one—are the trials included. In this paper, 52% of the trial participants were claudicants.
Rather than get caught up in appropriateness-of-use criteria, adherence to medical therapy and supervised exercise programs, I chose to eliminate that half of the study population from consideration. There is simply not enough information in this paper to make decisions for the treatment of claudicants.
In general, these non-invasive interventions work and we should focus more of our attention to these therapies. If you must intervene, then avoiding drug-coated technology and the stenting of femoropopliteal lesions is easy enough if you are as equally concerned about the possible amputation and mortality risks as I am.
Taking into consideration the 11 of 21 trials including mostly patients with CLTI, the authors report a 7.2% vs. 4.7% (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.04–2.33; p=0.03) risk of limb loss with the use of PCB angioplasty versus plain balloon angioplasty over one to two years.
While there may be increased risk of limb amputation at this point using PCBs compared to deploying plain balloons, these major limb amputation rates are remarkably low. Other registry studies report a major limb amputation rate as high as 20% within one year in patients with CLTI who are revascularized, and this is in line with the Society for Vascular Surgery (SVS) objective performance goals.
The authors report that the preponderance of trial participants were white males. That limits the generalizability of these results as we know that females are equally as likely to have PAD, and that Black females specifically have the highest rates of limb amputation after CLTI diagnosis.
Another major issue that limits my ability to interpret this data is the problem of imprecise language to define inclusion criteria trials of CLTI patients.
We need more precise information on wound size and location—and patient comorbid and anatomic factors—in order to really determine the expected risk of an adverse outcome, as well as whether or not a slightly higher risk is merited for each individual situation. As an example, many of the trials in this meta-analysis include “Rutherford 5/6” patients. We know that Rutherford 6 means an unsalvageable limb, so, clearly, patients with Rutherford 6 disease should not be included in a revascularization trial. This leaves the reader questioning who was actually included.
Limb outcomes are directly related to the severity of the wound at the time of revascularization, and until we start stratifying our analyses by the SVS WIfI (wound, ischemia, foot infection) wound classification system, we will not be able to determine the effect of other factors with a weaker signal, such as the paclitaxel dose administered.
To conclude, the authors raise an important concern that there may be downstream tissue effects of lower-extremity arterial paclitaxel administration. I agree with them that this is enough preliminary data to merit a dedicated trial to evaluate this specific safety question.
However, in the meantime, the majority of my patients with CLTI have a greater than 7.2% risk of limb loss within one or two years, and in cases of patients who are poor bypass candidates with moderate-large wounds and difficult-to-treat lesions like below-the-knee popliteal occlusion, I think it is reasonable to continue to use drug-coated technology as part of a multipronged strategy to treat CLTI.